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SPHINGOLIPID SIGNALING AND DISEASE: THE KEY ROLE OF CERAMIDE TRAFFIC IN CELL FATE REGULATION
Full text linkCancer and diabetes are among the most common diseases in western societies. Sphingolipids, a class of lipids ubiquitously present in eukaryotic membranes, play a key role in the regulation of different signal transduction pathways involved in the modulation of many cellular functions [1, 2]. The past two decades have seen increased interest in the bioactive sphingolipids ceramide (Cer) and sphingosine-1 phosphate (S1P). Cer, a central molecule of sphingolipid metabolism, is involved in the control of many cell-stress responses, including growth arrest, senescence and cell death [3]. On the other hand, several studies have proposed a crucial role of S1P in cell growth and survival, cell migration, angiogenesis, and inflamma¬tion [3]. Thus, Cer and S1P can differentially regulate cell death and survival by controlling opposing signaling pathways [4]. So far, a large amount of studies has clarified the complexity of the interplay between S1P, Cer and sphingolipid metabolism and these implications in the etiology of several human diseases. Effectively, deregulation of sphingolipid metabolism is implicated in numerous diseases, and accumulating evidence has shown a clear indication that sphingolipids have important role in the pathogenesis of diabetes and cancer [5].
Very recently, it is emerging a pivotal role of Cer traffic from the Endoplasmic Reticulum (ER) to the Golgi apparatus in the regulation of sphingolipid metabolism. In fact, Cer transport is a highly regulated step in the sphingolipid biosynthesis. Two main mechanisms are involved in Cer transport from ER to the Golgi apparatus: a protein-mediated transport, operated by CERT [6, 7] and a CERT-independent vesicular transport. Moreover, several studies reported that ER is a critical intracellular organelle involved in the control of cell fate [8, 9]. In this light, Cer accumulation in the ER appears to be a key element in the promotion of cell death in different human diseases, as well as in glioblastoma and diabetes.
In light of these findings, in my Ph.D. course I wanted to evaluate in cellular models of glioblastoma (GBM) and type 2 diabetes (T2D) the role of Cer transport in the regulation of cell fate.
Part 1: Glucolipotoxicity impairs ceramide flow from the ER to the Golgi apparatus in INS-1 -cells
T2D is the most common form of diabetes characterized by insulin resistance and β-cell dysfunction. The etiology of T2D is not well established but it is know that loss of insulin secretion is directly linked to a loss of function and death of pancreatic β-cells [10]. Glucolipotoxicity is a condition determined by the combined action of elevated glucose and free fatty acids (FFAs) levels that exerts deleterious effects on pancreatic -cell function and survival. Several mechanisms have been proposed for glucolipotoxicity-induced β-cell dysfunction, and, among them, ER stress and elevations of the proapoptotic sphingolipid Cer appear to play key roles. Moreover, Cer accumulation due to glucolipotoxicity can be associated to the induction of ER stress. As in other cells, in the INS-1 insulinoma cell line, two main mechanisms are involved in Cer transport from the ER to the Golgi apparatus: a CERT-mediated transport [6, 11], and a CERT-independent vesicular transport. Glucolipotoxic conditions, obtained with 0.4 mM palmitate and 30 mM glucose administration, strongly affected both of them by reducing CERT protein synthesis and activity, and the rate of Cer vesicular traffic, thus promoting Cer accumulation in the ER. [11, 12]. The two Cer transport mechanisms are effectively involved in the control of sphingolipid metabolism, participating in the regulation of Cer accumulation in the ER involved in pancreatic -cell function and death during T2D.
Part 2: The stimulation of Cer traffic from the ER to the Golgi apparatus S1P-dependent as a survival factor in T98G glioma cells.
GBM is the most common malignant primary brain tumor in adults and one of the most lethal human cancers [13]. S1P and Cer have emerged as bio-effectors molecules, involved in both glioblastoma development and resistance [3, 14-17]. Several lines of evidence indicated that, different anticancer drugs, including etoposide, exert cytotoxic effects also promoting accumulation of Cer in the ER. Thus, the transport of Cer from ER to Golgi apparatus could be represent a key pathway for limiting Cer accumulation in the ER and escape from cell death. Moreover, we recently demonstrated that vesicular-mediated Cer transport is positively regulated by the pro-survival pathway phosphatidylinositol 3-phosphate kinase (PI3K)/Akt [18], known effectors of extracellular S1P.
In T98G glioma cells, S1P treatment was able to increase vesicular Cer transport from the ER to the Golgi apparatus by PI3K/Akt pathway activation, inducing Cer conversion to SM and glycosphingolipids (GSL). In these cells, the cytotoxic Cer accumulation in the ER promoted by the anticancer drug etoposide was strongly reduced after S1P administration. S1P, by enhancing Cer traffic, act as pro-oncogenic factor, favoring both the reduction of the pro-apoptotic Cer at the ER and the synthesis of complex sphingolipids. By this mechanism S1P also stimulates the generation of new membranes, functional to cell growth and consequently to the tumor survival and progression
CYTOTOXIC EFFECTS OF PERIFOSINE IN HUMAN GLIOBLASTOMA CELLSARE ASSOCIATED TO AN ALTERED CERAMIDE METABOLISM
No full textBackground: Glioblastoma multiforme (GBM) is the most malignant brain tumor and, despite aggressive therapy, prognosis for patients is poor. Temozolomide (TMZ), the chosen drug in GBM therapy, exerts cytotoxic effects also through an increase of ceramide levels. Perifosine (PF) is currently being tested for treatment of major human cancers, but little is known about its efficacy in gliomas. The aim of this work is to evaluate in GBM cell lines if PF is able to regulate sphingolipid metabolism and to enhance the cytotoxic effect of TMZ.
Results: The results obtained demonstrated that in different GBM cell lines, the treatment with PF led to a dose-dependent decrease in cell viability. In all GBM cells lines, PF promoted a time-dependent decrease of p-Akt levels, with an about 50% decrease after 4 hour treatment. In these conditions, metabolic studies showed that treatment with PF significantly modified sphingolipid (SL) metabolism by inhibiting sphingomyelin (SM) and, in a lesser extent, glycosphingolipid (GSL) biosynthesis with a consequent accumulation of ceramide (Cer). In addition, PF weakly reduced sphingosine-1-phosphate (S1P) biosynthesis. The treatment with LY294002, in conditions giving an almost complete inhibition of the PI3K/Akt pathway, only partly mimicked the effects of PF on SL metabolism, suggesting that PF could regulate SL metabolism also through a mechanism other than Akt inhibition. In the same GBM cell lines, the treatment of PF in combination with TMZ had an additive, but not synergistic cytotoxic effect. More of interest, a TMZ resistant cell line, that is characterized by an altered SL profile, a high capacity to release S1P and in which TMZ is unable to accumulate Cer, was still sensitive to PF.
Conclusions: These data suggest that PF can exert its anticancer activity through a marked modulation of sphingolipid metabolism with increased Cer/S1P ratio, where Cer acts as a pro-death and S1P as a survival factor. PF in combination with TMZ could thus improve the treatment efficacy in GBM
Phosphatidylinositol 3-Kinase/AKT pathway regulates the endoplasmic reticulum to Golgi traffic of ceramide in glioma cells : a link between lipid signaling pathways involved in the control of cell survival
Full text linkDifferent lines of evidence indicate that both aberrant activation of the phosphatidylinositol 3-OH kinase (PI3K)/Akt survival pathway and down-regulation of the death mediator ceramide play a critical role in the aggressive behavior, apoptosis resistance, and adverse clinical outcome of glioblastoma multiforme. Furthermore, the inhibition of the PI3K/Akt pathway and the up-regulation of ceramide have been found functional to the activity of many cytotoxic treatments against glioma cell lines and glioblastomas as well. A reciprocal control between PI3K/Akt and ceramide signaling in glioma cell survival/death is suggested by data demonstrating a protective role of PI3K/Akt on ceramide-induced cell death in glial cells. In this study we investigated the role of the PI3K/Akt pathway in the regulation of the ceramide metabolism in C6 glioma cells, a cell line in which the PI3K/Akt pathway is constitutively activated. Metabolic experiments performed with different radioactive metabolic precursors of sphingolipids and microscopy studies with fluorescent ceramides demonstrated that the chemical inhibition of PI3K and the transfection with a dominant negative Akt strongly inhibited ceramide utilization for the biosynthesis of complex sphingolipids by controlling the endoplasmic reticulum (ER) to Golgi vesicular transport of ceramide. These findings constitute the first evidence for a PI3K/Akt-dependent regulation of vesicle-mediated movements of ceramide in the ER-Golgi district. Moreover, the findings also suggest the activation of the PI3K/Akt pathway as crucial to coordinate the biosynthesis of membrane complex sphingolipids with cell proliferation and growth and/or to maintain low ceramide levels, especially as concerns those treatments that promote ceramide biosynthesis in the ER
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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